The critical issue in the biology of herpes simplex virus (HSV) concerns the biochemical mechanism which determines the lytic-latent life cycle of the virus. Following a primary infection, an individual harbors the viral genome in the neurons of the sensory trigeminal/sacral) ganglia where it remains in a latent state until complex stimuli induce reactivation and viral replication. Little is known about the factors involved in determining the latent-lytic states of the virus, however, the expression of the viral Immediate Early genes may represent an important regulatory point in this process. Specifically, the C1 factor, a critical component of the herpes simplex virus enhancer complex that acts cooperatively with Oct-1 and VP16 to activate the expression of the viral immediate early genes may play a critical role in the determination of the latent-lytic viral cycle. As the virus does not establish latency in tissue culture systems, a mouse model system was established to analyze the role of the C1 factor in cellular processes and in the regulation of the latent-lytic cycle of HSV. In contrast to the ubiquitous nuclear expression of the C1 factor in the cells of most tissues, the protein is specifically sequestered in the cytoplasm of cells which harbor latent virus and is transported to the nucleus upon stimulation of viral reactivation. Furthermore, in latently infected ganglia, there is a complete correlation between neurons exhibiting C1 transport and neurons exhibiting viral reactivation from latency. In addition, a similar pattern of localization was found in human trigeminal ganglia, indicating that the C1 factor may represent a critical switch in determining the viral lytic/latent cycle.